Glutamate signaling in chondrocytes and the potential involvement of NMDA receptors in cell proliferation and inflammatory gene expression

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Abstract

Objective: Increased levels of glutamate, the main excitatory neurotransmitter, are found in the synovial fluid of osteoarthritis (OA) patients. Our aim was to study glutamate signaling in chondrocytes, focusing on the composition, pharmacology, and functional role of N-methyl-d-aspartate (NMDA) glutamate receptors. Methods: We used the human chondrocyte cell line SW1353 and, in parallel, primary rat articular chondrocytes. Glutamate release and uptake were measured by fluorimetric and radiometric methods, respectively. Gene expression was analyzed by quantitative polymerase chain reaction. NMDA receptor pharmacology was studied in binding experiments with [3H]MK-801, a specific NMDA receptor antagonist. RNA interference was used to knock-down the expression of NR1, a subunit of NMDA receptors. Results: Glutamate release, sodium- and calcium-dependent glutamate uptake, and the expression of a glutamate transporter were observed in chondrocytes. NR2D was the most abundant NMDA receptor subunit in these cells. Consistent with this observation, the binding affinity of [3H]MK-801 was much lower in chondrocytes than in rat brain membranes (mean Kd values of 700 and 2.6 nM, respectively). NR1 knock-down, as well as NMDA receptor blockade with MK-801, reduced chondrocyte proliferation. Interleukin (IL)-1β significantly altered glutamate release and uptake (about 90% increase and 50% decrease, respectively, in SW1353 cells). Moreover, IL-1β induced the gene expression of cytokines and enzymes involved in cartilage degradation, and MK-801 significantly inhibited this response. Conclusions: Our findings suggest that chondrocytes express a self-sufficient machinery for glutamate signaling, including a peripheral NMDA receptor with unique properties. This receptor may have a role in the inflammatory process associated with cartilage degradation, thus emerging as a potential pharmacological target in OA. © 2009 Osteoarthritis Research Society International.

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Piepoli, T., Mennuni, L., Zerbi, S., Lanza, M., Rovati, L. C., & Caselli, G. (2009). Glutamate signaling in chondrocytes and the potential involvement of NMDA receptors in cell proliferation and inflammatory gene expression. Osteoarthritis and Cartilage, 17(8), 1076–1083. https://doi.org/10.1016/j.joca.2009.02.002

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